Immunologically-silent phagocytosis of apoptotic cells is critical for neurogenesis, tissue homeostasis, injury repair and innate immune balance. Inefficient microglial phagocytic clearance is a general mechanism of secondary microglial activation, inflammation and tissue damage, leading to neuropathological exacerbation and scar formation in inflammatory neurodegenerative diseases, spinal cord injury and hemorrhagic stroke. For example, mutations of phagocytic receptor TREM2 with unknown ligands impair microglial phagocytosis and upregulate pro-inflammatory cytokines, leading to a chronic and fatal neurodegenerative disease by undefined mechanisms. The critical barrier to defining microglial dysfunction in senescent and disease conditions is our current inability to systematically map phagocytosis ligands for different receptors and quantify the activities of different signaling pathways. The long-term goal of this project is to globally map phagocytosis signaling pathways for comprehensive understanding of microglial dysfunction and exploit their therapeutic potentials with identified phagocytosis ligands. The objective is to globally identify TREM2-specific phagocytosis ligands by a new paradigm of phagoligandomics and validate their biological relevance. The hypothesis will be investigated with the following aims. Aim 1: To test the prediction that the new paradigm of phagoligandomics globally maps microglial TREM2 ligands and defines microglial dysfunction. Aim 2: To test the prediction that identified proteins are biologically-relevant TREM2 ligands. The outcomes of this project include the first ever ligandomics for global mapping of cell-wide phagocytosis ligands and receptor-specific ligands. Phagoligandomics will globally map phagocytosis pathways to provide molecular insights into microglial clearance of superfluous neurons during neurogenesis and quantitatively define microglial dysfunction in senescent and disease conditions, including TREM2 mutations. Identified ligands will improve our capability to harness the therapeutic potentials of microglial phagocytosis by facilitating debris clearance and preventing microglial activation in neurological diseases.